Razak, Albiruni Ryan Abdul

359881 Background: Sunitinib is approved for advanced gastrointestinal stromal tumor (GIST) after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor (TKI), is indicated for the treatment of adult patients (pts) with GIST who received prior treatment with 3 or more TKIs, including imatinib. We compared the efficacy and safety of ripretinib vs sunitinib in pts with advanced GIST who progressed on or were intolerant to imatinib. Methods: This multicenter, global, randomized, open-label phase 3 study (NCT03673501) enrolled adult pts with GIST who progressed on or had intolerance to imatinib. Pts were randomized 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Randomization was stratified by KIT mutational status and imatinib intolerance. The primary endpoint was progression-free survival (PFS) by independent radiologic review (IRR) using modified RECIST version 1.1. Key secondary endpoints were objective response rate (ORR) by IRR and overall survival (OS). Hierarchical testing was performed for primary and key secondary endpoints in a prespecified sequence; testing pts with a KIT exon 11 primary mutation (Ex11 intention-to-treat [ITT] population) preceded the all-patient (AP) ITT population. Data cutoff was 1 Sep 2021; final analyses of PFS and ORR and the first interim analysis of OS were conducted. Results: A total of 453 pts were randomized to ripretinib (n = 226; Ex11 ITT, n = 163) or sunitinib (n = 227; Ex11 ITT, n = 164). Median age was 60 yrs (range 18–88) and most pts were white (66.2%) males (62.0%). PFS was not statistically different between ripretinib and sunitinib in the Ex11 ITT (hazard ratio [HR] 0.88, 95% CI 0.66, 1.16; P = 0.36; median 8.3 vs 7.0 mos) or in the AP populations (HR 1.05, 95% CI 0.82, 1.33; P = 0.72; median 8.0 vs 8.3 mos). ORR was numerically higher for ripretinib vs sunitinib in the Ex11 ITT (23.9% vs 14.6%; difference 9.3%, 95% CI 0.7, 17.8; nominal P = 0.03) and AP ITT populations (21.7% vs 17.6%; difference 4.2%, 95% CI −3.2, 11.5; nominal P = 0.27). OS data was highly immature; median OS was not reached in either arm. Fewer pts in the ripretinib arm experienced Grade 3-4 (G3-4) treatment-emergent adverse events (TEAEs) vs sunitinib (41.3% vs 65.6%). Among G3-4 TEAEs with a difference ≥5% between arms, ripretinib had fewer events vs sunitinib (hypertension [8.5% vs 26.7%], palmar-plantar erythrodysesthesia [1.3% vs 10.0%], neutropenia [0% vs 6.3%], and neutrophil count decreased [0% vs 7.2%]). Conclusions: The PFS in both arms was longer than PFS achieved by sunitinib in its pivotal phase 3 trial. While the PFS for ripretinib did not meet the primary endpoint of superiority vs sunitinib, meaningful clinical activity and fewer G3-4 TEAEs were observed in pts with advanced GIST treated with ripretinib after imatinib failure. Clinical trial information: NCT03673501.

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

11504 Background: This phase 2, open-label trial (SPEARHEAD-1; NCT04044768) is designed to evaluate the efficacy, safety, and tolerability of afamitresgene autoleucel in 45 patients (pts) with advanced/metastatic synovial sarcoma or Myxoid/Round Cell Liposarcoma (MRCLS). Methods: Eligible pts are HLA-A*02 positive with MAGE-A4-expressing tumors. Pts undergo leukapheresis for collection of autologous T-cells for processing and manufacture into afamitresgene autoleucel cells. Pts were treated with afamitresgene autoleucel doses between 1–10 × 109 transduced T-cells after receiving lymphodepleting chemotherapy. The primary endpoint is overall response rate per RECIST v1.1 by independent review. An independent Data Safety Monitoring Board reviews ongoing safety and benefit: risk during the interventional phase. Results: As of Feb 4, 2021, 32 pts received afamitresgene autoleucel. Of these pts, 59% were male, 87.5% had synovial sarcoma, the median age was 43 yrs (range: 24–73), and they had a median of 3 prior systemic lines of therapy. The MAGE-A4 antigen expression level (histoscore) ranged from 112–300, and the transduced cell dose ranged from 2.7–9.9 x 109. At the data cutoff, 25 pts were evaluable for preliminary efficacy (23 with synovial sarcoma and 2 with MRCLS) and 7 pts (5 with synovial sarcoma and 2 with MRCLS) had insufficient follow-up (<8 weeks follow-up and/or awaiting first scan). Of the 25 evaluable pts, the investigator-assessed responses were: complete response (2 pts), partial response (8 pts), stable disease (11 pts), and progressive disease (4 pts). All responses were confirmed. Nine of the 10 responders had ongoing response at the data cutoff and 3 responders had MAGE-A4 antigen histoscores <200. The most common AEs of any grade (>30% pts) were neutropenia, lymphopenia, nausea, cytokine release syndrome, leukopenia, fatigue, pyrexia, and anemia. Cytokine release syndrome of any grade occurred in 19/32 pts; 95% of those events were ≤Grade 2. No immune effector cell-associated neurotoxicity syndrome (ICANS) has been reported to date. Cytopenia (≥G3) at 4 wks post-infusion was observed in 6 pts (anemia 3 pts, neutropenia 2 pts, and thrombocytopenia 1 pt). Conclusion: These preliminary data demonstrate afamitresgene autoleucel is efficacious and well tolerated in heavily pre-treated pts. Objective responses are reported across a wide range of MAGE-A4 antigen levels and deep responses have been observed. Initial durability data is encouraging. Preliminary response data in SPEARHEAD-1 is comparable to the findings of the prior Phase 1 trial [1]. To date, the safety profile of afamitresgene autoleucel has been favorable, with mainly low-grade cytokine release syndrome and tolerable/reversible hematologic toxicities. [1]. Van Tine BA, et al. CTOS; November 18-21, 2020; Virtual. Clinical trial information: NCT04044768.